EP0239605A1 - Strukturen zur gesteurten freisetzung von chemischen stoffen. - Google Patents

Strukturen zur gesteurten freisetzung von chemischen stoffen.

Info

Publication number
EP0239605A1
EP0239605A1 EP19860905895 EP86905895A EP0239605A1 EP 0239605 A1 EP0239605 A1 EP 0239605A1 EP 19860905895 EP19860905895 EP 19860905895 EP 86905895 A EP86905895 A EP 86905895A EP 0239605 A1 EP0239605 A1 EP 0239605A1
Authority
EP
European Patent Office
Prior art keywords
layer
release
soluble
substance
layers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP19860905895
Other languages
English (en)
French (fr)
Other versions
EP0239605B1 (de
Inventor
Adrian Leonard Collum En Mears
John David Britten Dr Benjamin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Qinetiq Ltd
Original Assignee
UK Secretary of State for Defence
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UK Secretary of State for Defence filed Critical UK Secretary of State for Defence
Publication of EP0239605A1 publication Critical patent/EP0239605A1/de
Application granted granted Critical
Publication of EP0239605B1 publication Critical patent/EP0239605B1/de
Expired legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor

Definitions

  • sustained and predictable release of a chemical For many applications it is desirable to obtain sustained and predictable release of a chemical. This is especially true in the case of drugs where it is desirable to maintain a well-controlled and stable release rate while avoiding the need for regular administration of the drug.
  • the second uses diffusion through a membrane, eg using patches containing the drug which are affixed to the outside of the skin. The drug perfuses through the skin at a steady rate. This is easily administered but duration and the range of possible drugs is limited.
  • a third approach is to incorporate the drug in a matrix (usually a polymer) which is formed into a pellet and implanted surgically or by means of a hypodermic device.
  • a matrix usually a polymer
  • the chief problem is that tne surface area of the pellet, and thus the release rate of tne drug, decrease with time.
  • plastic would be to sputter a ceramic layer, eg a few microns of silicon nitride, again keeping one or both ends clear so that the metal can be dissolved out through them.
  • a ceramic layer eg a few microns of silicon nitride
  • This invention therefore consists of a method of fabricating a structure for the controlled release of a substance located in the structure between two relatively insoluble layers, characterised, in that a first relatively insoluble layer, a soluble layer containing the substance to be released and a second relatively insoluble layer are deposited sequentially on a substrate, followed by the removal of the substrate, the shapes of the layers being such that the soluble layer is entirely surrounded by the relatively insoluble layers except for one or more release orifices.
  • the said substance is in direct contact with the outside through the orifice in the structure, so that on coming into contact with a solvent, the substance is released through the orifice at a rate proportional to the surface area in contact with the solvent.
  • the rate of release may be varied as a function of time.
  • a layer of a different material of known solubility is interposed between the two insoluble layers, the said material interconnecting the orifice with one or mere substances whose release, is to be controlled, whereby a delayed and/or alternating release may be obtained.
  • a plurality of such structures may be fabricated on a single substrate and by layer processing technology a large number of very small structures may be produced.
  • the substance may be formed in a matrix the breakdown of which will release the substance.
  • Figures 1 and 2 are respectively longitudinal vertical and horizontal schematic sections of a basic structure for the con trolled release of a substance
  • Figure 3 is a corresponding horizontal section through a structure in which the rate of release of the substance is periodic
  • Figure 4 is a longitudinal vertical section through a structure in which two different substances are released alternately
  • Figures 5, 6 and 7 illustrate in detail three steps in the fabrication of a structure such as that illustrated in Fig 4,
  • Figure 8 illustrates a small structure which is designed to release a drug a certain time after application
  • Figure 9 is a plan view of a device actuated by the receipt of a radio signal
  • Figures 10 and 11 are sections at slightly enlarged scales of the device illustrated in Figure 9 along the lines 10-10 and 11-11 respectively, and Figure 12 illustrates schematically equipment incorporating theinvention for performing chemical assays.
  • Example 1
  • a reservoir of material containing the drug can be sandwiched between. two layers of relatively insoluble material as illustrated in Figs 1 to 4.
  • the shape of the reservoir layer can be chosen so as to achieve whatever is desired as a function of time, but in general the reservoir layer 1 contains tne drug incorporated in a slowly soluble material and is surrounded, entirely except at one edge 3, by a layer or layers 2 of a relatively insoluble material.
  • the reservoir in the structure of Figs 1 and 2 can be folded back onto itself or into a spiral, giving a much longer drug release period for a device of a given size and given rate of dissolution of the material in which the drug is incorporated.
  • Such structures can be made by exploiting the layer processing technology used in the fabrication of integrated circuits, thin film and thick film hybrids and pcbs.
  • the steps involved are: 1. Take a substrate made of a material which can be dissolved without affecting the material of which the particles are to be made, or deposit a layer of such a material on top of a bulk substrate.
  • a structure of the type illustrated in Fig 4 can be made by the following stages, with reference to Figs 5, 6 and
  • the rubber layer provides protection and biocompatibility while the metal layers act as a diffusion barrier and ensure that the only way that the drug can escape is through the polyanhydride dissolving, this exposing the drugs which then also dissolve.
  • the size and shape of the particles is accurately determined by physical (primarily lithographic) processes. It is also possible to make particles of more than one size and shape at the same time.
  • Relatively complicated particles can be made if desired.
  • a drug can be released which will cause cells to stop at a particular stage in their division cycle followed by another drug which will kill cells at this point. This is useful in cancer treatment.
  • the devices may be placed in a body cavity, or injected (eg intramuscularly or subcutaneously) through a hypodermic needle. In the latter case, the use of a large number of small capsules (typically with a diameter of less than 500 microns) is necessary so they will go down the needle. Similar devices may be incorporated into coverings for burn wounds so as to release an antibiotic, eg penicillin, at a steady rate to prevent infection.
  • an antibiotic eg penicillin
  • Example 3 Rather than depositing all the drug in the same place, it may be desirable to achieve distributed release throughout the body in order to avoid local concentration build-up.
  • the drug can be incorporated into a large number of small particles of the type described in Example 1 which can be either inhaled or injected into the bloodstream or into body cavities joints, the genito-urinary tract or fluids eg the cerebro spinal fluid. The particles will then release their payloads in a predetermined way, controlled by the structure of the devices, over the extended region over which they are distributed.
  • Example 3
  • particles similar to those described in Example 1 except in the respect that the particles carry a layer of antibody over part or all of their surface so that they stick to particular sites, eg tumours (in this case employing PLAP - placental alkaline phosphatase, HMFG - human milk fat globulin, CEA - Carcino-Embrionic antibody, HCG - Human Chorionic Gonadotrophin), so that these parts of the body receive more dosage than the rest.
  • tumours in this case employing PLAP - placental alkaline phosphatase, HMFG - human milk fat globulin, CEA - Carcino-Embrionic antibody, HCG - Human Chorionic Gonadotrophin
  • the surfaces can be coated by known technidues with a lipid layer to which antibodies are attached.
  • These particles need to be administered so that they are distributed over the region of interest and preferably so that they will move through it, thereby maximising the chance of their encountering the target tissue.
  • the particles need to be minute (less than 5 microns in their maximum dimension) in order to go through capillaries, and it may be desirable just to perfuse them through the limb or organ of interest in a limited circulation, thereby avoiding the lungs, liver and spleen where they are liable to be trapped.
  • a reservoir 16 of drug-containing material 0.4 micron thick ana 1 micron long, is deposited on a slowly soluble layer 17, 0.2 micron thick and longer in one direction by 0.7 micron.
  • These two layers are formed as a thin gold layer 18 on the surface of a 0.1 micron thick insoluble layer.
  • a top coating of insoluble material, 0.1 micron thick, is formed over the reservoir 16 and extends 0.5 micron- beyond the edge of the reservoir leaving the end 0.2 micron of the slowly soluble layer 17 exposed.
  • the slowly soluble material 17 therefore has to dissolve back 0.5 micron before the drug can be dissolved out, thereby providing the time delay.
  • Example 5 The release of drugs in parts of the body in which particular conditions, eg pH, are met by means of structures in which the drug is only exposed to the environment once a material which is only soluble in the particular conditions has dissolved. Apart from this requirement the structures are the same as those of Figs 1 to 4 and the slowly soluble polymer may be chosen to be soluble only under the appropriate conditions. Polymers whose solution rate is strongly pH dependent are particularly suitable.
  • Example b
  • radioactive or neutron activated species may be incorporated directly in one of the layers, or inserted by ion implantation.
  • antibody-labelled devices For combining radiotherapy with chemotherapy, eg against cancer, antibody-labelled devices can be employed which release cnemicals and also, for example, contain polonium 210. This is a pure alpha emitter so only the immediate surrounding tissue is irradiated.
  • a gamma-emitter For radiolabelling a gamma-emitter is used.
  • One example of the incorporation of a gamma emitter is to implant 2 x 10 16 cm -2 arsenic 75 ions into the devices and to perform the neutron activation at a flux of 5 x 10 12 neutrons cm- 2 s -1 for 24 hours. This will transmute roughly 1 atom in 10 6 of the arsenic 75 to arsenic 76 whicn is a gamma emitter with a half life of 26.5 hours.
  • Other nuclei which are also suitable for neutron activation into gamma emitters are tabulated below.
  • Example 7 Combining drug release witn a label to make it easier to see where tne particles have reached.
  • the particles can incorporate a layer of a heavy element eg lead, platinum or gold (typically also acting as a, relatively insoluble layer or diffusion barrier in a structure of the type shown in Figs 7 and 8) to enhance the particles X-ray absorption.
  • a heavy element eg lead, platinum or gold
  • Alternative labels are fluorescence, and elements which provide nuclear magnetic resonance and electron spin resonance signals.
  • the structure is 0.5mm long and has on it a nichrome aerial 20, feeding into a resistive load 21 consisting of a fine wire composed of nichrome 0.5 micron thick, 1 micron wide and 100 microns long which goes to and fro across a 20 micron square area, providing a resistive load of 200 ohms.
  • meltable plug 22 eg of a hydrocarbon wax
  • a meltable plug 22 eg of a hydrocarbon wax
  • greater heating could be achieved using pulsed illumination, eg 10 microseconds on, 10 ms off.
  • the mean power which can be safely dissipated is a constant (typically 1.2kWm -2 is a limitation in the body) but the temperature is proportional to the Guty cycle ratio (in this case 1000 times which would yield 2000°C - enough not only to melt the plug but also to flash evaporate it and the nichrome).
  • the voltage generated is proportional to aerial length and the load impedance of a matched load is inversely proportional to it so the power available is proportional to length -3 x illuminating frequency (assuming that the illuminsating frequency is still low compared with that at which the aerial is resonant).
  • Alternatives to melting are the use of a suitable phase change or thermal expansion to rupture the containment and allow the drug to escape. Structures of this type could be administered to a body in the manner of Example 2 or Example 3, and be set off on command by a burst of microwave radiation.
  • a particular use, especially as the devices are made smaller, is to coat them with an antibody, allow some time for them to stick to a target tissue and then illuminate the area of interest within the body , causing those devices within this region to release their chemical.
  • a minimum practicable size of device using microwave-based release is roughly 80 microns long.
  • a further means of targeting is to incorporate the particles into a phagocytic (eg a polymorphonuclear) cell by separating out cells from a sample of the patient's blood, allowing the cells to injest the devices and reinjecting them into the patient.
  • the phagocytic cells will then migrate to the site of infection, such as an abcess. If the devices release their payload after a time delay of typically 4 hours, then most of the cells will by then have reached their target and the drug will have been applied selectively.
  • Example 10 The use of structures of the type shown in Example 1 to release corrosion-inhibiting additives into engine cooling water or engine oil eg in car and aero engines.
  • Example 10 The use of structures of the type shown in Example 1 to release corrosion-inhibiting additives into engine cooling water or engine oil eg in car and aero engines.
  • Example 10 The use of structures of the type shown in Example 1 to release corrosion-inhibiting additives into engine cooling water or engine oil eg in car and aero engines.
  • non-medical examples, of applications of the invention include the following: 1. Antifoulants, especially for marine use, where they may be incorporated into paint and the chemical released at a sufficient rate to prevent the growth of barnacles and the like. This may require release sustained over a period of years. The frequency with which repainting is needed and the pollution due to excessive release when the paint is new are problems with anti-foulant paint currently available.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • General Physics & Mathematics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
EP19860905895 1985-10-02 1986-10-02 Strukturen zur gesteurten freisetzung von chemischen stoffen Expired EP0239605B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8524369 1985-10-02
GB858524369A GB8524369D0 (en) 1985-10-02 1985-10-02 Structures

Publications (2)

Publication Number Publication Date
EP0239605A1 true EP0239605A1 (de) 1987-10-07
EP0239605B1 EP0239605B1 (de) 1992-07-08

Family

ID=10586108

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19860905895 Expired EP0239605B1 (de) 1985-10-02 1986-10-02 Strukturen zur gesteurten freisetzung von chemischen stoffen

Country Status (5)

Country Link
EP (1) EP0239605B1 (de)
CA (1) CA1280073C (de)
DE (1) DE3685957T2 (de)
GB (1) GB8524369D0 (de)
WO (1) WO1987001937A1 (de)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3764018A (en) * 1971-06-15 1973-10-09 Union Carbide Corp Fluid transfer membrane use thereof and method of manufacture therefor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8701937A1 *

Also Published As

Publication number Publication date
DE3685957T2 (de) 1993-01-14
WO1987001937A1 (en) 1987-04-09
DE3685957D1 (de) 1992-08-13
CA1280073C (en) 1991-02-12
EP0239605B1 (de) 1992-07-08
GB8524369D0 (en) 1985-11-06

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